BIOCHEMICAL EVALUATION OF ADRENERGIC FUNCTION

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The main objectives are to develop and apply methods for biochemical evaluation of catecholaminergic neuronal function. By the use of radioactively labelled amines and/or measurements of levels of DOPA, dopamine, norepinephrine, epinephrine and their metabolites in body fluids (CSF, plasma, urine), rates of amine formation and metabolism are estimated. Relative changes in rates of formation of the amines are selected metabolites provide indices of brain dopaminergic or noradrenergic activity or peripheral sympathoadrenal medullary function. Use of 18F-labelled dopamine is being developed for PET scanning of peripheral sympathetic activity in vivo. The rate of release of norepinephrine from sympathetic nerve terminals is reflected partially by spillover of the released catecholamine into plasma, but only a small and somewhat variable portion reaches the circulation. By examining, after prelabelling with 3H-dopamine, the relative specific activities of 3H-norepinephrine and its major intraneuronal metabolite, DHPG, it was concluded that in the sympathetic nerves of the isolated rat vas deferens there are at least two vesicular storage sites for norepinephrine. Plasma levels of DOPA also provide an index of catecholamine formation. The release of norepinephrine into the synapse is dependent upon outflow of impulses from the spinal cord, but is regulated also by negative feedback through presynaptic alpha-2 adrenoceptor stimulation by the released catecholamine. Fluorinated derivatives of DOPA and dopamine have been shown to be metabolized similarly to their parent compounds. Studies of urinary excretion of dopamine and norepinephrine metabolites in patients with orthostatic hypotension suggested that homovanillic acid is derived from dopamine formed in sympathetic neurons as well as from dopamine formed in dopaminergic neurons. Pharmacological inhibition with Debrisoquin of formation of catechols in peripheral tissues is attended by decreases in both dopamine and norepinephrine metabolites. The decline in excretion (or plasma levels) of these metabolites is not proportionately equal because HVA production in the brain is unaffected by debrisoquin. We have shown that HVA excretion attributable to brain dopamine is diminished by about 75% in MPTP treated monkeys, consistent with the extensive destruction of the nigrostriatal dopaminergic neurons which contain about 80% of brain dopamine. These data provide the basis for a method now being used to estimate the rate of HVA production in brains of humans at different ages or with neurological disorders.